Endocrinol Metab.  2025 Feb;40(1):135-145. 10.3803/EnM.2024.2040.

Triiodothyronine Is Associated with Incidence/Resolution of Steatotic Liver Disease: Longitudinal Study in Euthyroid Korean

• Kim HI
• Kim JY
• Cho JH
• Han JM
• Suh S
• Bae JC
• Kim TH
• Kim SW
• Hahm JR
• Chung JH

• KMID: 2565261
• DOI: http://doi.org/10.3803/EnM.2024.2040

Abstract

Background
The positive relationship between triiodothyronine (T3) and steatotic liver disease (SLD) demonstrated only in crosssectional study. We aimed to evaluated whether total T3 (TT3) is associated with the development/resolution of SLD in longitudinal design.
Methods
This retrospective, longitudinal, population-based cohort study included 1,665 South Korean euthyroid adults with ≥4 thyroid function test. We explored the impact of mean TT3 during follow-up on development/resolution of either SLD (diagnosed by ultrasound) or modified metabolic dysfunction-associated steatotic liver disease (MASLD) using Cox proportional hazards regression models.
Results
During about median 5 years follow-up, 807/1,216 (66.3%) participants among participants without SLD at baseline developed SLD, and 253/318 (79.5%) participants among participants with SLD at baseline SLD resolved fatty liver. Mean TT3 rather than thyroid stimulating hormone or mean free thyroxine was significantly related with development (adjusted hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00 to 1.02; P=0.002) and resolution (adjusted HR, 0.97; 95% CI, 0.96 to 0.99; P=0.005) of SLD. Compared with low mean TT3 group, high mean TT3 group was positively associated with development of SLD (adjusted HR, 1.20; 95% CI, 1.05 to 1.38; P=0.008) and inversely associated with resolution of SLD (adjusted HR, 0.66; 95% CI, 0.51 to 0.85; P=0.001). The statistical significance remained for development (adjusted HR, 1.29; 95% CI, 1.10 to 1.51; P=0.001) and resolution (adjusted HR, 0.71; 95% CI, 0.54 to 0.94; P=0.018) of modified MASLD.
Conclusion
In Korean euthyroid adults, TT3 level was associated with development and resolution of either SLD or modified MASLD.

Keyword

Thyroid hormones; Triiodothyronine; Fatty liver; Longitudinal studies

Figure

• 

  Fig. 1. Study flow diagram. GNUH, Gyeongsang National University Hospital; USG, ultrasonography; TFT, thyroid function test; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; LC, liver cirrhosis; HCC, hepatocellular carcinoma; SLD, steatotic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease.

• 

  Fig. 2. Kaplan–Meier graphs for the development of fatty liver in participants with body mass index (A) <23 (n=557), (B) 23–25 (n=338), and (C) ≥25 kg/m2 (n=437) according to mean total triiodothyronine (TT3) status.

• 

  Fig. 3. Kaplan–Meier graphs for the development of fatty liver in the (A) body weight loss group (n=267), (B) body weight stable group (n=745), and (C) body weight gain group (n=320) according to mean total triiodothyronine (TT3) status.

Reference

1. Lee NH, Jeong SJ, Wang JH, Choi YJ, Oh HM, Cho JH, et al. The clinical diagnosis-based nationwide epidemiology of metabolic dysfunction-associated liver disease in Korea. J Clin Med. 2023; 12:7634.

2. Younossi ZM, Alqahtani SA, Alswat K, Yilmaz Y, Keklikkiran C, Funuyet-Salas J, et al. Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease. J Hepatol. 2024; 80:419–30.

3. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023; 78:1966–86.

4. Cordeiro A, Souza LL, Einicker-Lamas M, Pazos-Moura CC. Non-classic thyroid hormone signalling involved in hepatic lipid metabolism. J Endocrinol. 2013; 216:R47–57.

5. van Tienhoven-Wind L, Dullaart RP. Low normal thyroid function as a determinant of increased large very low density lipoprotein particles. Clin Biochem. 2015; 48:489–94.

6. De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf). 2007; 67:265–9.

7. Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol. 2010; 316:165–71.

8. Roef G, Lapauw B, Goemaere S, Zmierczak HG, Toye K, Kaufman JM, et al. Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men. Eur J Endocrinol. 2012; 167:719–26.

9. van den Berg EH, van Tienhoven-Wind LJ, Amini M, Schreuder TC, Faber KN, Blokzijl H, et al. Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study. Metabolism. 2017; 67:62–71.

10. Liu G, Zheng X, Guan L, Jiang Z, Lin H, Jiang Q, et al. Free triiodothyronine levels are positively associated with nonalcoholic fatty liver disease in euthyroid middle-aged subjects. Endocr Res. 2015; 40:188–93.

11. Rudorff KH. Thyroxine-binding globulin (TBG): clinical studies on the regulation of TBG concentration in serum and the value of TBG for the evaluation of thyroid function. Fortschr Med. 1979; 97:2038–45.

12. Farrell GC, Chitturi S, Lau GK, Sollano JD; Asia-Pacific Working Party on NAFLD. Guidelines for the assessment and management of non-alcoholic fatty liver disease in the Asia-Pacific region: executive summary. J Gastroenterol Hepatol. 2007; 22:775–7.

13. Pan WH, Yeh WT. How to define obesity?: evidence-based multiple action points for public awareness, screening, and treatment: an extension of Asian-Pacific recommendations. Asia Pac J Clin Nutr. 2008; 17:370–4.

14. Williamson DA, Bray GA, Ryan DH. Is 5% weight loss a satisfactory criterion to define clinically significant weight loss? Obesity (Silver Spring). 2015; 23:2319–20.

15. Kushner RF, Ryan DH. Assessment and lifestyle management of patients with obesity: clinical recommendations from systematic reviews. JAMA. 2014; 312:943–52.

16. Chen P, Hou X, Wei L, Feng L, Zhong L, Jiao L, et al. Free triiodothyronine is associated with the occurrence and remission of nonalcoholic fatty liver disease in euthyroid women. Eur J Clin Invest. 2019; 49:e13070.

17. Ittermann T, Haring R, Wallaschofski H, Baumeister SE, Nauck M, Dorr M, et al. Inverse association between serum free thyroxine levels and hepatic steatosis: results from the Study of Health in Pomerania. Thyroid. 2012; 22:568–74.

18. Tao Y, Gu H, Wu J, Sui J. Thyroid function is associated with non-alcoholic fatty liver disease in euthyroid subjects. Endocr Res. 2015; 40:74–8.

19. Taylor PN, Richmond R, Davies N, Sayers A, Stevenson K, Woltersdorf W, et al. Paradoxical relationship between body mass index and thyroid hormone levels: a study using mendelian randomization. J Clin Endocrinol Metab. 2016; 101:730–8.

20. Ferrannini E, Iervasi G, Cobb J, Ndreu R, Nannipieri M. Insulin resistance and normal thyroid hormone levels: prospective study and metabolomic analysis. Am J Physiol Endocrinol Metab. 2017; 312:E429–36.

21. Wolffenbuttel BH, Wouters HJ, Slagter SN, van Waateringe RP, Muller Kobold AC, van Vliet-Ostaptchouk JV, et al. Thyroid function and metabolic syndrome in the population-based LifeLines cohort study. BMC Endocr Disord. 2017; 17:65.

22. Xia SF, Qiu YY, Chen LM, Jiang YY, Huang W, Xie ZX, et al. Myricetin alleviated hepatic steatosis by acting on microRNA-146b/thyroid hormone receptor b pathway in high-fat diet fed C57BL/6J mice. Food Funct. 2019; 10:1465–77.

23. Alonso-Merino E, Martin Orozco R, Ruiz-Llorente L, Martinez-Iglesias OA, Velasco-Martin JP, Montero-Pedrazuela A, et al. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. Proc Natl Acad Sci U S A. 2016; 113:E3451–60.

24. Ritter MJ, Amano I, Hollenberg AN. Thyroid hormone signaling and the liver. Hepatology. 2020; 72:742–52.

25. Mendoza A, Hollenberg AN. New insights into thyroid hormone action. Pharmacol Ther. 2017; 173:135–45.

26. Ishizuka T, Lazar MA. The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor. Mol Endocrinol. 2005; 19:1443–51.

27. Nannipieri M, Cecchetti F, Anselmino M, Camastra S, Niccolini P, Lamacchia M, et al. Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss. Int J Obes (Lond). 2009; 33:1001–6.

28. Cho SW. Selective agonists of thyroid hormone receptor beta: promising tools for the treatment of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2024; 39:285–7.

29. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024; 390:497–509.

30. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004; 14:635–7.

31. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006; 239:105–12.

32. McPherson S, Jonsson JR, Cowin GJ, O’Rourke P, Clouston AD, Volp A, et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol. 2009; 51:389–97.